Spiro[cyclopent[b]indole-piperidines]

ABSTRACT

Novel spiro[cyclopent[b]indole-piperidines], intermediates and processes for the preparation thereof, and methods of relieving memory dysfunction and treating depression utilizing the spiro[cyclopent[b]indole-piperidines] and intermediates, or compositions thereof are disclosed.

[0001] This application claims the benefit of Provisional Application(Serial No. not yet assigned), filed Apr. 10, 1996.

[0002] The present invention relates tospiro[cyclopent[b]indole-piperidines]. More particularly, the presentinvention relates to spiro[cyclopent[b]indole-piperidines] of formula 1

[0003] wherein X is hydrogen, halogen, loweralkoxy, loweralkyl, hydroxy,trifluoromethyl and m is 1 or 2 or a group of the formula

[0004] wherein R is loweralkyl and R₃ is hydrogen or loweralkyl; R₁ ishydrogen or loweralkyl; R₂ is hydrogen, a group of the fornula

[0005] wherein n is 1 or 2 and X and m are as above, a group of theformula

[0006] wherein X and m are as above, or a group of the formula

[0007] wherein X and m are as above, Y is hydrogen, or a group of theformula

[0008] wherein R₄ is hydrogen or loweralkyl and p is 2 or 3; the opticalisomers thereof; or the pharmaceutically acceptable acid addition saltsthereof useful in relieving memory dysfunction and thus indicated in thetreatment of Alzheimer's disease, as well as useful in the treatment ofdepression.

[0009] Subgeneric to the compounds of formula 1 are those wherein R₂ ishydrogen or a group of the formula

[0010] The present invention relates to (N′-phenyl)hydrazones of formula2

[0011] wherein R₂ is hydrogen or loweralkyl; R₅ is hydrogen orloweralkyl; and X is hydrogen, halogen, loweralkoxy, loweralkyl, hydroxyor trifluoromethyl and m is 1 or 2; the optical isomers thereof; or thepharmaceutically acceptable salts thereof, useful as intermediates forthe preparation of the spiro[cyclopent[b]indole-piperidines] of formula1 and also for the treatment of depression, and 4-yanopiperidines offormula 3

[0012] wherein R₆ is loweralkyl; and R₇ is halogen or cyano, useful asintermediates for the preparation of thespiro[cyclopent[b]indole-piperidines] of formula 1.

[0013] As used throughout the specification and appended claims, theterm “alkyl” refers to a straight or branched chain hydrocarbon radicalcontaining no saturation and having 1 to 8 carbon atoms. Examples ofalkyl groups are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-hexyl,3-hexyl, 4-heptyl, 2-octyl and the like. The term “alkoxy” refers to amonovalent substituent which consists of an alkyl group linked throughan ether oxygen having its free valence bond from the ether oxygen.Examples of alkoxy groups are methoxy, ethoxy, propoxy, 1-butoxy,1-pentoxy, 3-hexoxy, 4-heptoxy, 2-octoxy and the like. The term“alkanol” refers to a compound formed by a combination of an alkyl groupand hydroxy radical. Examples of alkanols are methanol, ethanol, 1- and2-propanol, 2,2-dimethylethanol, hexanol, octanol and the like. The term“halogen” refers to a member of the family fluorine, chlorine, bromine,or iodine. The term “lower” as applied to any of the aforementionedgroups refers to a group having a carbon skeleton containing up to andincluding 6 carbon atoms.

[0014] The compounds of the present invention which lack an element ofsymmetry exist as optical antipodes and as the racemic forms thereof.The optical antipodes may be prepared from the corresponding racemicforms by standard optical resolution techniques, involving, for example,the separation of diastereomeric salts of those instant compoundscharacterized by the presence of a basic amino group and an opticallyactive acid, or by synthesis from optically active precursors.

[0015] The present invention comprehends all optical isomers and racemicforms thereof of the compounds disclosed and claimed herein and theformulae of the compounds shown herein are intended to encompass allpossible optical isomers of the compounds so depicted.

[0016] The novel spiro[cyclopent[b]indole-piperidines] of the presentinvention are prepared by the processes delineated in Reaction Scheme A.

[0017] To prepare a spiro[cyclopent[b]indole-piperidine] of formula 1 an8-azaspiro[4.5]decane-1-one 4 is condensed with a phenylhydrazine offormula 5

[0018] wherein R₁ is hydrogen or loweralkyl and X and m are as above toprovide a phenylhydrazone of formula 2 wherein R₁, X and m are as above,which is cyclized to a spiro[cyclopent[b]indole-piperidine] 1 whereinR₁, X and m are as above and R₂ is hydrogen. The condensation is carriedout by treating the cyclopentanone 4 with a phenylhydrazine 5 in thepresence of an organic carboxylic acid such as acetic acid or a mineralacid such as hydrochloric acid in an alkanol such as ethanol at anelevated temperature such as that within the steam bath range to provide2.

[0019] The cyclization is accomplished by treating a phenylhydrazone 2with an aqueous alkanolic mineral acid such as ethanolic hydrogenchloride at a temperature within the steam bath range to provide 1.

[0020] To fabricate a 1′-benzoylspiro[cyclopent[b]indole-piperidine] 1wherein R₁ is lowerakyl, R₂ is

[0021] and X, m and n are as above or a1′-phenylethylspiro[cyclopent[b]indole-piperidine] 1 wherein R₁ isloweralkyl and R₂ is

[0022] wherein X, m and n are as above, aspiro[cyclopent[b]indole-piperidine] 1 wherein R₁ is loweralkyl, R₂ ishydrogen and X and m are as above is treated with a benzoyl halide offormula 6

[0023] wherein X and m are as above and Hal is bromo or chloro or apnenylalkyl halide of formula 7

[0024] wherein X, m, n and Hal are as above in the presence of atriloweralkylamine such as triethylamine in a halocarbon solvent such asdichioromethane at a temperature within the range from about 0° C. toabout ambient temperature, or an alkali metal carbonate such aspotassium carbonate in an organic solvent such as acetonitrile at atemperature of about the reflux temperature of the reaction medium.

[0025] Similarly, a 1′-phenoxyalkylspiro[cyclopent[b]indole-piperidine]1 wherein R₁ is loweralkyl and R₂ is a group of the formula

[0026] wherein X and m are as above, Y is hydrogen or a group of theformula

[0027] wherein R₄ is hydrogen or loweralkyl and p is 2 or 3 is preparedby treating a spiro[cyclopent[b]indole-piperidine] 1 wherein R₁ ishydrogen or loweralkyl, R₂ is hydrogen and X and m are as above with aphenoxyalkyihalide of formula 8

[0028] wherein X, Y, m, p and Hal are as above and an inorganic basesuch as cesium carbonate in an organic solvent such as acetonitrile at atemperature of about 80° C.

[0029] The preparation of the starting material,8-azaspiro[4,5]decane-1-one 4, for the elaboration of the spiro[cyclopentd indole-piperidines] of the present invention is outlined inReaction Scheme B and exemplified in the Examples. In this process,commercially available 4-acetamiddopiperidine 9 is acylated toN-ethoxycarbonyl-4-acetamidopiperidine 10, which in turn is converted to4-cyano-N-ethoxycarbonylpiperdine 11 and then alkylated to4-(3-chloropropyl)-4-cyano-N-ethoxycarbonylpiperidine 12.4-(3-Chloropropyl)4-cyano-N-ethoxycarbonylpiperidine 12 is converted to4-cyano-4-(3-cyanopropyl)-N-ethoxycarbonyl piperidine 13, which iscyclized to 4-cyano-1-imino-8-azaspiro[4,5]decane 14 and hydrolyzedto 1. While the process for the synthesis of the starting material 4 forthe preparation of the ultimate spiro[cyclopent[b]indole-piperidines] 1is illustrated with N-ethoxycarbonylpiperidines (10 to 14), the schemeis equally applicable for N-loweralkoxycarbonylpiperidines.

[0030] The spiro[cyclopent[b]indole-piperidines] and related compoundsof the present invention are useful as agents for the relief of memorydysfunction, particularly dysfunctions associated with decreasedcholinergic activity such as those found in Alzheimer's disease. Reliefof memory dysfunction activity is demonstrated in the in vitroinhibition of acetylcholinesterase assay, an assay for the determinationof the ability of a drug to inhibit the inactivation of acetylcholine, aneurotransmitter implicated in the etiology of memory dysfunction andAlzheimer's dementia. In this assay, a modification of a test describedby G. L. Ellman, et al., Biochemical Pharmacology, 7, 88 (1961), thefollowing reagents are prepared and employed:

[0031] 1. 0.005M Phosphate Buffer (pH 7.2)

[0032] A solution of monobasic sodium phosphate monohydrate (6.85 g) indistilled water (100 ml) is added to a solution of dibasic sodiumphosphate heptahydrate (13.4 g) and distilled water (100 ml) until a pHof 7.2 was attained. The solution was diluted 1 to 10 with distilledwater.

[0033] 2. Substrate in Buffer

[0034] The 0.05M Phosphate Buffer (pH 7.2) was added toacetylthiocholine (198 mg) to a total volume of 100 ml, i.e., a quantitysufficient (gs) to 100 ml.

[0035] 3. 5,5-Dithiobisnitrobenzoic Acid in Buffer

[0036] The 0.05M Phosphate Buffer (pH 7.2) was added to5.5-dithiobisnitrobenzoic acid to a total volume of 100 ml, i.e., aquantity sufficient (gs) to 100 ml.

[0037] 4. Stock Solution of Drug

[0038] A 2 millimolar stock solution of the test drug is prepared in aquantity sufficient of either acetic acid or dimethyl sulfoxide tovolume with 5,5-dithiobisnitrobenzoic acid in Buffer. Stock Solution ofDrug is serially diluted (1:10) so that the final cuvette concentrationis 10⁻⁴ molar.

[0039] Male Wistar rats are decapitated, brains rapidly removed, corporastriata dissected free, weighted and homogenized in 19 volumes(approximately 7 mg protein/ml) of 0.05M Phosphate Buffer (pH 7.2) usinga Potter-Elvejhem homogenizer. A 25 μl aliquot of this suspension isadded to 1 ml of the vehicle or various concentrations of the test drugand preincubated for 10 minutes at 37° C. Enzyme activity is measuredwith a Beckman DU-50 spectrophotometer with the following software andinstrument settings:

[0040] 1. Kinetics Soft-Pac™ Module #598273;

[0041] 2. Program #6 Kindata;

[0042] 3. Source—Vis;

[0043] 4. Wavelength—412 nm;

[0044] 5. Sipper—none;

[0045] 6. Cuvettes—2 ml cuvettes using auto 6-sampler;

[0046] 7. Blank—1 for each substrate concentration;

[0047] 8. Interval time—15 seconds (15 or 30 seconds for kinetics);

[0048] 9. Total time—5 minutes (5 to 10 minutes for kinetics);

[0049] 10. Plot—yes;

[0050] 11. Span—autoscale;

[0051] 12. Slope—increasing;

[0052] 13. Results—yes (gives slope); and

[0053] 14. Factor—1.

[0054] Reagents are added to the blank and sample cuvettes as follows:

[0055] 1. Blank:

[0056] 0.8 ml 5-5-Dithiobisnitrobenzoic Acid

[0057] 0.8 ml Substrate in Buffer

[0058] 2. Control: 0.8 ml 5.5-Dithiobisnitrobenzoic Acid/Enzyme

[0059] 0.8 ml Substrate in Buffer

[0060] 3. Drug: 0.8 ml 5.5-Dithiobisnitrobenzoic Acid/Drug/Enzyme

[0061] 0.8 ml Substrate in Buffer

[0062] Blank values are determined for each run to control fornon-enzymatic hydrolysis of substrate and these values are automaticallysubtracted by the Kindata program available on kinetics soft-pac module.This program also calculates the rate of absorbance change for eachcuvette.

For IC₅₀ Determinations

[0063] Substrate concentration is 10 millimolar diluted 1:2 in assayyielding final concentration of 5 millimolar. 5,5-dithiobisnitrobenzoicacid concentration is 0.5 millimolar yielding 0.25 millimolar finalconcentration.${\% \quad {Inhibition}} = {\frac{{{Slope}\quad {Control}} - {{Slope}\quad {drug}}}{{Slope}\quad {Control}} \times 100}$

[0064] IC₅₀ values are calculated from log-probit analysis TABLE IInhibition of Acetyl- choline- sterase Activity Compound IC₅₀(μM)1,4-dihydro-7-methoxy-4-methyl-1′-phenylmethylspiro 23.6[cyclopent[b]indole-3(2H),4′-piperidine]1,4-dihydro-7-hydroxy-4-methyl-1′-phenylmethylspiro 20.4[cyclopent[b]indole-3(2H),4′-piperidine]1,4-dihydro-4-methyl-7-methylaminocarbonyloxy-1′- 10.5phenylmethylspiro[cyclopent[b]indole-3(2H),4′-piperidine1,4-dihydro-7-dimethylaminocarbonyloxy-4-methylspiro 64.0[cyclopent[b]indole-3(2H),4′-piperidine1,4-dihydro-4-methylspiro[cyclopent[b]indole-3(2H), 84.1 4′-piperidine]1,4-dihydro-4-methyl-1′-(4-methoxyphenyl)methylspiro 65.2[cyclopent[b]indole-3(2H),4′-piperidine] tacrine (reference) 0.31

[0065] Relief of memory dysfunction is achieved when the presentspiro[cyclopent[b]indole-piperidines] and related compounds areadministered to a subject requiring such treatment as an effective oral,parenteral or intravenous dose of from 0.10 to 50 mg/kg of body weightper day. A particularly effective amount is about 10 mg/kg of bodyweight per day. It is to be understood, however, that for any particularsubject, specific dosage regimens should be adjusted according to theindividual need and the professional judgment of the personadministering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and that they do not, to any extent, limit thescope or practice of the invention.

[0066] The spiro[cyclopent[b]indole-piperidines] of the presentinvention are also useful as agents for treating depression. Depressiontreatment is demonstrated in the in vitro inhibition of monoamineoxidase assay, an assay for the determination of the ability of a drugto inhibit the enzyme monoamine oxidase. In this assay, a modificationof an assay described by M. V. Kindt, et al., Europ. J. Pharmnacol. 146:313-318 1988.

[0067] The following reagents are prepared:

[0068] 1. Phosphate buffer (0.5 M), pH 7.4; 134.4 g dibasic sodiumphosphate heptahydrate q.s. to 1 liter in distilled water (A) 17.3 gmonobasic sodium phosphate q.s. to 250 ml in distilled water (B) AdjustpH of A to 7.4 by slowly adding B (volumes as needed) Dilute 1:10 indistilled water (0.05 M phosphate buffer, pH 7.4)

[0069] 2. 0.25 M Sucrose (phosphate buffered): 21.4 g sucrose, q.s. to250 nil with 0.05 M phosphate buffer

[0070] 3. Substrate for monoamine oxidase-A:

[0071] a. serotonin creatine sulphate (5-hydroxytryptamine) is obtainedfrom Sigma Chemical Company. A 5 mM stock solution ig made up in 0.01N-hydrochloric acid. The solution is used to dilute the specificactivity of the [³H]-hydroxytryptamine.

[0072] b. [³H]-5-hydroxytryptamine binoxalate (20-30 Ci/mmol) isobtained from New England Nuclear.

[0073] c. Add 12 μl of [³H]-5-hydroxytryptamine to 2 ml of the 5 mM5-hydroxytryptamine solution. (Final amine concentration in the assay is200 μM: see below.)

[0074] 4. Substrate for monoamine oxidase-B

[0075] a. β-phenethylamine is obtained from Sigma Chemical Company. A 5mM stock solution is made up in 0.01 N-hydrochloric acid. The solutionis used to dilute the specific activity of the [¹⁴C]-β-phenethylamine.

[0076] b. β-[ethyl-1-¹⁴C]-phenethylamine hydrochloride (40-50 mCi/mmol)is obtained from New England Nuclear.

[0077] c. Add 12 μl of [¹⁴C]-β-phenothylaamine to 2 ml of the 5 mMβ-phenethylamine solution. (Final amine concentration in the assay is200 μM: see below.)

[0078] 5. Equal amounts of monoamine oxidase-A (5-hydroxyttyptamine) andmonoamine oxidase-B (β-phenethylamine) substrates are combined forsimultaneously testing both monoamine oxidase types, i.e., mixed stocksolution of 2.5 mM 5-hydroxytryptamine and 2.5 mM β-phenethylamine. 40μl of this mixed solution gives a 200 μM final concentration of eachamine in the assay. When testing only one monoamine oxidase type, theindividual 5 mM stock solutions must be diluted 1:1 with distilled waterprior to adding 40 μl to the incubation mixture; i.e., same 200 μM finalamine concentration.

[0079] 6. Stock solutions of test drugs are made up in appropriatevehicles and serially diluted to give final concentrations ranging from10⁻⁷ to 10⁻³ molar in the assay. Lower concentrations can be made formore potent drugs.

[0080] Tissue Preparation

[0081] Male Wistar rats weighing 150-250 grams were sacrificed and thebrains rapidly removed. Whole brain minus cerebellum was homogenized in30 volumes of ice-cold, phosphate-buffered 0.25 M sucrose, using aPotter-Elvejhem homogenizer. The homogenate was centrifuged at 1000 gfor 10 minutes and the supernatant (S₁) decanted and recentrifuged at18,000 g for 20 minutes. The resulting pellet (P₂) was resuspended infresh 0.25 M sucrose and serves as the tissue source for mitochondrialmonoamine oxidase.

[0082] C. Assay

[0083] 10 μl 0.5 M phosphate buffer, pH 7.4

[0084] 50 μl water or appropriate drug concentration

[0085] 400 μl tissue suspension

[0086] Tubes are preincubated for 15 minutes at 37° C. and the assay isstarted by adding 40 μl of combined substrate ([³H]-5-hydroxytryptamineand [¹⁴C]-β-phenethylamin) at 15 second intervals. The tubes areincubated for 30 minutes at 37° C. and the reaction stopped by theaddition of 0.3 ml 2N-hydrochloric acid. Tissue blank values aredetermined by adding the acid before the radioactive substrate. Theoxidative products of the reaction are extracted withethylacetate/toluene (1:1). Add 5 mnl of this mixture to the tubes,vortex for 15 seconds to extract the deaminated metabolites into theorganic phase and allow to separate from the aqueous phase. Place tubesin acetone/dry ice bath to freeze the aqueous layer. When this layer isfrozen, pour off the top organic layer into a scintillation vial. Add 10ml Liquiscint and count the samples using window settings for ¹⁴C in onechannel and ³H in the second channel. IC₅₀ values are determined bylog-probit analysis.

[0087] Results TABLE II Mono- Mono- amine amine Oxidase IC₅₀ OxidaseCompound A (μM) B 8-azaspiro[4,5]decane-1-[N′- 37.2 3.7(4-methoxy)phenyl]hydrazone 1,4-dihydro-1′-(3-methoxyphenyl)methyl-4-51.2 — methylspiro[cyclopent[b]indole-3(2H), 4′-piperidine1,4-dihydro-1′-(4-methoxyphenyl)methyl- 98.6 124.64-methylspiro[cyclopent[b]indole-3-(2H), 4′piperidine] brofaromine(reference) 0.18 23.4

[0088] Depression treatment is achieved when the presentspiro[cyclopent[b]indole-piperidines] and related compounds areadministered to a subject requiring such treatment as an effective oral,parenteral or intravenous dose of from 0.10 to 50 mg/kg of body weightper day. A particularly effective amount is about 10 mg/kg of bodyweight per day. It is to be understood, however, that for any particularsubject, specific dosage regimens should be adjusted according to theindividual need and the professional judgment of the personadministering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and that they do not, to any extent, limit thescope or practice of the invention.

[0089] Acetylcholinesterase inhibitors and monoamine oxidase inhibitorsare known in the art as being useful as relievers of memory dysfunctionand as antidepressants, respectively. (See V. Kumar in Alzheimer'sDisease: Therapeutic Strategies, E. Giacobini and R. Becker Eds.;Birkhauser, Boston 1994 for memory dysfunction utility and K F. Tiptonin Biochemical and Pharmacological Aspects of Depression, K. F. Tiptonand U. B. H. Youdin, Eds., Taylor and Francis, London 1989 forantidepressant utility.

[0090] Effective amounts of the compounds of the invention may beadministered to a subject by any one of various methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions. The free base final products, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable addition salts for purposes of stability,convenience of crystallization, increased solubility and the like.

[0091] Preferred pharmaceutically acceptable addition salts includesalts of mineral acids, for example, hydrochloric acid, sulfuric acid,nitric acid and the like, salts of monobasic carboxylic acids such as,for example, acetic acid, propionic acid and the like, salts of dibagiccarboxylic acids such as, for example, maleic acid, fumaric acid, oxalicacid and the like, and salts of tribasic carboxylic acids such as, forexample, carboxysuccinic acid, citric acid and the like.

[0092] The active compounds of the present invention may be administeredorally, for example, with an inert diluent or with an edible carrier.They may be enclosed in gelatin capsules or compressed into tablet. Forthe purpose of oral therapeutic adm;nistration, the aforesaid compoundsmay be incorporated with excipients and used in the form of tablets,troches, capsules, elixirs, suspensions, syrups, wafers, chewing gumsand the like. These preparations should contain at least 0.5% of activecompounds, but may be varied depending upon the particular form and mayconveniently be between 4% to about 75% of the weight of the unit. Theamount of present compound in such composition is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 mgs of active compound.

[0093] The tablets, pills, capsules, troches and the like may alsocontain the following ingredients: a binder such as microcrystallinecellulose, gum tragacanth or gelatin; an excipient such as starch orlactose, a disintegrating agent such as alginic acid, Primogel, cornstarch and the like; a lubricant such as magnesium stearate or Sterotes;a glidant such as colloidal silicon dioxide; and a swcctcning agent suchas sucrose or saccharin or a flavoring agent such as peppermint, methyl,salicylate, or orange flavoring may be added. When the dosage unit is acapsule it may contain, in addition to materials of the above type, aliquid carrier such as fatty oil. Other dosage unit forms may containother various materials which modify the physical form of the dosageunit, for example, as coatings. Thus tablets or pills may be coated withsugar, shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

[0094] For the purposes of parenteral therapeutic administration, theactive compounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of theaforesaid compound, but may be varied between 0.5 and about 50% of theweight thereof. The amount of active compound in such compositions issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 mgs of the activecompound.

[0095] The solutions or suspensions may also include the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; antibacterial agents such as benzyl alcoholor methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. Theparenteral preparations can be enclosed in ampules, disposable syringesor multiple vials made of glass or plastic.

[0096] The following examples are for illustrative purposes only and arenot to be construed as limiting the invention in any way whatsoever.

EXAMPLE 1 1,4-Dihydrospiro[cyclopent[b]indole-3(2H),4′-piperidine]hydrochloride hemihydrate

[0097] A solution of 8-azaspiro[4,5]decane-1-(N′-phenyl)hydrazonehydrochloride (1.0g) in ethanolic hydrochloric acid (15 ml) was heatedon a steam bath for 90 min, with stirring, and then concentrated invacuo. The residue was flash chromatographed (silica gel), eluting with15% methanol/dichloromethane. The appropriate fractions were collectedand concentrated. The residue was recrystallized from ethanol/ethylacetate to give 0.4 g (43%) of product, mp 315-316° C.

[0098] Analysis:

[0099] Calculated for C₁₅H₁₈N₂.HCl.1/2H₂O: 66.29%C 7.42%H 10.31%N

[0100] Found: 66.16%C 7.19%H 10.18%N

EXAMPLE 2 1′-Benzoyl-1,4-dihydrospiro[cyclopent[b]indole-3(2H),4′-piperidine]

[0101] To a solution of 1,4-dihydrospiro[cyclopent[b]indole-3(2H),4′-pipendine] hydrochloride (1.0 g) and potassium carbonate (0.8 g) inacetonitrile (10 ml) was added benzoyl chloride (0.5 g), under nitrogen,with stirring. The reaction mixture was heated under reflux for 5 hrsand allowed to cool to ambient temperature. Ethyl acetate (200 ml) wasadded, and the mixture was washed with water and saturated sodiumhydroxide solution, dried over anhydrous magnesium sulfate, filtered andthe filtrate was concentrated in vacua. The residue was flashchromatographed (silica gel), eluting with 0.5%methanol/dichloromethane. The appropriate fractions were collected andconcentrated to give 0.40 g (33%) of product, mp 231-232° C.

[0102] Analysis:

[0103] Calculated for C₂₂H₂₂N₂: 79.97%C 6.71%H 8.48%N

[0104] Found: 79.67%C 6.74%H 8.43%N

EXAMPLE 3 1,4-Dihydro-7-methoxyspiro[cyclopent[b]indole-3(2H),4′-piperdine]hydrochloride

[0105] A solution of8-azaspiro[4,5]decane-1-[N′-(4-methoxy)phenyl]hydrazone hydrochloride(2.0 g) in ethanolic hydrochloric acid (10 ml) and water (0.5 ml) washeated on a steam bath for 1 hr, with stirring, and then concentrated invacuo. The residue was flash chromatographed (silica gel), eluting with5% methanol/dichloromethane, The appropriate fractions were collectedand concentrated. The residue was recrystallized from ethanol to give0.5 g (26%) of product mp>280° C.

[0106] Analysis:

[0107] Calculated for C₁₆H₂₀N₂O.HCl: 65.63%C 7.23%H 9.57%N

[0108] Found: 65.52%C 7.49%H 9.54%N

EXAMPLE 41-[4-[3-(7-Fluoro-1,4-dihydrospiro[cyclopent[b]indole-3(2H),4′-piperidine]-1′-yl)propoxy]-3-methoxyphenl]ethanonehydrate

[0109] To a solution of1,4-dihydro-7-fluorospiro[cyclopent[b]indole-3(2H), 4′-piperidine] (3.00g) in acetonitrile (30 ml) was added cesium carbonate (6.97 g) and1-[4-(3-bromopropoxy)-3-methoxyphenyl]ethanone (3.38 g), under nitrogen,with stirring. The reaction mixture was heated at 80° C. for 3 hrs andallowed to cool to ambient temperature. The mixture was extracted withethyl acetate. The extracts were washed with water, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated in vacuo.The residue was flashed chromatographed (silica gel) eluting with 1%acetone/dichloromethane. The appropriate fractions were collected andconcentrated to give 1.00 g (30%) of product, mp 165- 166° C.

[0110] Analysis:

[0111] Calculated for C₂₇H₃₁FN₂O₃.H₂O: 69.21%C 7.10%H 5.98%N

[0112] Found: 69.00%C 6.85%H 5.82%N

EXAMPLE 5 1,4-Dihydro-4-methylspiro[cyclopent[b]indole-3(2H),4′-piperidine]hydrochloride

[0113] A solution of 8-azaspiro[4,5]decane-1-one hydrochloride (5.2 g)in 95% ethanolic hydrochloric acid (30 ml) and1-methyl-1-phenylhydrazine (5 g) was heated overnight on a steam bath,under nitrogen. The reaction mixture was cooled to ambient temperature,methanol was added and the mixture was concentrated in vacuo. Theresidue was flash chromatographed (silica gel) eluting with 10%methanol/dichloromethane. The appropriate fractions were collected andconcentrated to afford 7.4 g (95%) of product, mp>270° C.

[0114] Analysis:

[0115] Calculated for C₁₆H₂₀N₂.HCl: 69.43%C 7.65%H 10.12%N

[0116] Found: 68.90%C 7.55%H 9.94%N

EXAMPLE 61,4-Dihydro-1′-(3-methoxyphenyl)methyl-4-methylspiro[cyclopent[b]indole-3(2H),4′piperidine]

[0117] A solution of 1,4-dihydro4-methylspiro[cyclopent[b]indole-3(2H),4′-piperidine] (2.5 g) and triethylamine (2.9 ml) in dichloromethanc(100 ml) and 3-(chloromethyl)anisole (1.95 g) was stirred overnight atambient temperature, under nitrogen. Saturated sodium chloride solutionwas added and the mixture was extracted with dichloromethane. Theextracts were dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated in vacuo. The residue was flashedchromatographed (silica gel), eluting with 10% anhydrousacetone/dichloromethane. The appropriate fractions were collected andconcentrated to give 1.3 g (35%) of product, mp 100-101° C.

[0118] Analysis:

[0119] Calculated for C₂₄H₂₈N₂O. 79.96%C 7.83%H 7.77%N

[0120] Found: 79.63%C 7.80%H 7.67%N

EXAMPLE 71,4-Dihydro-7-methoxy-4-methylspiro[cyclopent[b]indole-3(2H),4′-piperidine]hydrochloride

[0121] A solution of8-azaspiro[4,5]decane-l-[N′-(4-methoxy)phenyl-N′-methyl]hydrazonehydrochloride (2.5 g) in ethanolic hydrochloric acid (20 ml) and water(0.5 ml) was heated on a steam bath for 1 hr, with stirring, and thenconcentrated in vacuo. The residue was flash chromatographed (silicagel), eluting with 10% methanol/dichloromethane. The appropriatefractions were collected and concentrated. The residue wasrecrystallized from ethanol to give 1.1 g (46%) of product, mp 278-279°C.

[0122] Analysis:

[0123] Calculated for C₁₇H₂₂N₂O.HCl: 66.55%C 7.56%H 9.13%N

[0124] Found: 66.45%C 7.86%H 9.14%N

EXAMPLE 81′-Benzoyl-1,4-dihydro-7-methoxy-4-methylspiro[cyclopent[b]indole-3(2H),4′-piperidine]hydrate

[0125] To a solution of1,4-dihydro-7-methoxy-4-methylspiro[cyclopent[b]indole-3(2H),4′-piperidine] hydrochloride (0.50 g) and triethylamine (0.33 g) indichloromethane (50 ml) was added benzoyl chloride (0.23 g) at 0° C.,under nitrogen, with stirring. The reaction mixture was stirred for 5hrs at ambient temperature. Dichloromethane (200 ml) was added and themixture was washed with water and saturated sodium chloride solution.The organic layer was dried over anhydrous magnesium sulfate, filtered,and the filtrate was concentrated in vacuo. The residue was flashchromatographed (silica gel), eluting with 5% ethylacetate/dichloromethane. The appropriate fractions were collected andconcentrated to give 0.40 g (66%) of product, mp 197-198° C.

[0126] Analysis:

[0127] Calculated for C₂₄H₂₆N₂O₂.H₂O: 73.44%C 7.19%H 7.14%N

[0128] Found: 73.90%C 6.76%H 6.95%N

EXAMPLE 91,4-Dihydro-7-methoxy-4-methyl-1′-phenylmethylspiro[cyclopent[b]indole-3(2H),4′-piperidine]hydrochloride

[0129] To a solution of1,4-dihydro-7-methoxy4-methylspiro[cyclopent[b]indole-3(2H),4′-piperidine hydrochloride (0.50 g) and triethylamine (0.33 g) indichloromethane (50 ml) was added benzyl bromide (0.28 g) at 0° C.,under nitrogen, with stirring. The reaction mixture was stirred for 72hrs at ambient temperature. Dichloromethane (200 ml) was added and themixture was washed with water and saturated sodium chloride solution.The organic layer was dried over anhydrous sodium sulfate, filtered, andthe filtrate was concentrated in vacuo. The residue was flashchromatographed (silica gel), eluting with 25% ethylacctate/dichloromethane. The appropriate fractions were collected andconcentrated. The residue was dissolved into ethyl acetate and treatedwith ethereal hydrogen chloride. The precipitate was recrystallized fromethanol/ethyl acetate to give 0.40 g (68%) of product, mp 253-254° C.

[0130] Analysis:

[0131] Calculated for C₂₄H₂₈N₂O.HCl: 72.62%C 7.36%H 7.06%N

[0132] Found: 72.23%C 7.51%H 6.99%N

EXAMPLE 101,4-Dihydro-7-hydroxy-4-methyl-1′-phenylmethylspiro[cyclopent[b]indole-3(2H),4′-piperidine hydrochloride

[0133] A solution of1,4-dihydro-7-methoxy-4-methyl-1′-phenylmethylspiro[cyclopent[b]indole-3(2H),4′-piperidine (1.7 g) and 48% hydrobromic acid (10 ml) was heated to 95°C., under nitrogen, with stirring. The reaction mixture was stirred for3 hrs. Dichloromethane (150 ml) was added, and the mixture was washedwith saturated sodium bicarbonate solution and saturated sodium chloridesolution. The layers were separated and the organic layer was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated invacuo. The residue was flash chromatographed (silica gel), eluting with25% ethyl acetate/dichloromethane. The appropriate fractions werecollected and concentrated. This free base was converted to thehydrochloride salt to give 1.3 g (80%) of product, mp 189-190° C.

[0134] Analysis:

[0135] Calculated for C₂₃H₂₆N₂O.HCl: 72.14%C 7.11%H 7.32%N

[0136] Found: 71.72%C 7.34%H 7.21%N

EXAMPLE 111,4-Dihydro-4-methyl-7-methylaminocarbonyloxy-1′-phenylmethylspiro[cyclopent[b]indole-3(2H),4′-piperidine]

[0137] To a solution of1,4-dihydro-7-hydroxy-4-methyl-1′-phenylmethylspiro[cyclopent[b]indole-3(2H),4′-pipezidine] (0.25 g) and copper (I) chloride (0.01 g) indichloromethane (10 ml) was added methyl isocyanate (0.04 g), undernitrogen, with stirring. The reaction mixture was stirred for 24 hrs.The mixture was flash chromatographed (neutral alumina) and eluted with25% ethyl acetate/dichloromethane. The appropriate fractions werecollected and concentrated to give 0.2 g (69%) of product, mp 189-190°C.

[0138] Analysis:

[0139] Calculated for C₂₅H₂₉N₃O₂: 74.41%C 7.24%H 10.41%N

[0140] Found: 74.04%C 7.05%H 10.16%N

EXAMPLE 121,4-Dihydro-7-dimethylaminocarbonyloxy-4-methylspirorcyclopentfblindole-3(2H),4′-piperidine]hemihydrate

[0141] To a solution of1,4-dihydro-7-hydroxy4-methylspiro[cyclopent[b]indole-3(2H),4′-piperidine] (0.61 g) and cesium carbonate (1.55 g) in acetonitrile(100 ml) was added dimethylcarbamyl chloride (0.25 g), under nitrogen,with stirring. The reaction mixture was stirred for 24 hrs, diluted withethyl acetate, and the mixture was washed with saturated sodium chloridesolution. The layers were separated, and the organic layer was driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated in vacuo. The residue was flash chromatographed (silica),eluting with 5% methanol/dichloromethane. The appropriate fractions werecollected and concentrated. The residue was recrystallized from ethylacetate/petroleum ether. The precipitate was flash chromatographed(silica), eluting with 25% ethyl acetateldichloromethane to give 0.1 g(15%) of product, mp 110-111° C.

[0142] Analysis:

[0143] Calculated for C₁₉H₂₅N₃O₂.1/2H₂O: 68.83%C 7.79%H 12.49%N

[0144] Found: 68.73%C 7.97%1H 12.44%N

EXAMPLE 131,4-Dihydro-1′-(4-methoxyphenyl)methyl-4-methylspiro[cyclopent[b]indole-3(2H),4′-piperidine]

[0145] A solution of 1,4-dihydro-4-methylspiro[cyclopent[b]indole-3(2H),4′-piperidine] (2.5 g) and triethylamine (2.9 ml) in dichioromethane(100 ml) and 4-(chloromethyl)anisole (1.95 g) was allowed to standovernight at ambient temperature, under nitrogen, with stirring.Saturated sodium chloride solution was added and the mixture wasextracted with dichloromethane. The layers were separated, and theorganic phase was dried over anhydrous magnesium sulfate and filtered.The filtrate was concentrated in vacuo. The residue was flashchromatographed (silica gel), eluting with 7.5% acetone/dichloromethane.The appropriate fractions were collected and concentrated to give 1.5 g(40%) of product, mp 39-40° C.

[0146] Analysis:

[0147] Calculated for C₂₄H₂₈N₂O: 79.96%C 7.83%H 7.77%N

[0148] Found; 79.65%C 7.92%H 7.64%N

EXAMPLE 14 Ethyl 4-(3-chloropropyl)-4-cyano-1-piperidinearboxylate

[0149] To a solution of ethyl 4-cyano-1-piperidinecarboxylate (6.0 g) intetrahydrofuran (120 ml) at −70° C., under nitrogen, was added asolution of lithium diisopropylamide (4.6 g) in tetrahydrofuran (21.5ml), dropwise, with stirring. The reaction was allowed to warm to −10°C. and after 30 min was recooled to −70° C. A solution of1-chloro-3-iodopropane (7.4 g) in tetrahydrofuran (20 ml) was added tothe mixture over 30 min. The reaction mixture was quenched with waterand allowed to warm to ambient temperature. The mixture was extractedwith ethyl acetate. The extracts were washed with water, saturatedsodium chloride solution, dried over anhydrous magnesium sulfate andfiltered. The filtrate was concentrated in vacuo and the residue wasflash chromatographed (silica), eluting with 2:1 heptane/ethyl acetate.The appropriate fractions were collected and concentrated to afford 5.5g (64%) of product.

[0150] Analysis:

[0151] Calculated for C₁₂H₁₉ClN₂O₂: 55.70%C 7.40%H 10.83%N

[0152] Found: 55.88%C 7.67%H 10.80%N

EXAMPLE 15 Ethyl 4-(3-cyanopropyl)-4-cyano-1-piperidinecarboxylate

[0153] To a solution of ethyl4-(3-chloropropyl)-4-cyano-1-piperidinecarboxylate (12.7 g) indimethylformamide (250 ml) was added sodium cyanide (24 g) undernitrogen, with stirring. The mixture was warmed at 140° C. overnight andthen cooled to ambient temperature, diluted with water and extractedwith ethyl acetate. The organic extracts were washed with saturated,sodium chloride solution and water, dried over anhydrous magnesiumsulfate and filtered. The filtrate was concentrated in vacuo. Theresidue was chromatographed, eluting with 2:1 heptane/ethyl acetate. Theappropriate fractions were collected and concentrated to give 10.8 g(88.5%) of product. A portion was distilled to give the analyticalsample, bp 196-201° C. (4 mm of mercury).

[0154] Analysis:

[0155] Calculated for C₁₃H₁₉N₃O₂: 62.63%C 7.68%H 16.85%N

[0156] Found: 62.27%C 7.85%H 16.63%N

EXAMPLE 16 8-Azaspiro[4,5]decane-1-[N′-(4-bromo)phenyl]hydrazonehydrochloride

[0157] To a solution of 8-azaspiro[4,5]decane-1-one hydrochloride (2.5g) in 95% ethanol (10 ml) was added acetic acid (0.5 ml) and4-bromophenylhydrazine (2.5 g), under nitrogen, with stirring. Themixture was heated on a steam bath for 20 min, cooled to 0° C. andfiltered. The filter cake was washed with IM hydrochloric acid solutionand chilled ethanol (10 ml) and dried in vacuo to give 4.2 g (89%) ofproduct, mp 285-286° C.

[0158] Analysis:

[0159] Calculated for C₁₅H₂₁BrClN₃: 50.23%C 5.90%H 11.71%N

[0160] Found: 50.36%C 6.04%H 11.45%N

EXAMPLE 17 8-Azaspiror4,5]decane-1-[N′-(4-methoxy)phenyl]hydrazonehydrochloride

[0161] To a solution of 8-azaspiro[4,5]decane-1-one hydrochloride (2.5g) in 95% ethanol (10 ml) was added acetic acid (0.5 ml) and4-methoxyphenylhydrazine (1.8 g), under nitrogen, with stirring. Themixture was heated on a steam bath for 15 min., cooled to 0° C. andfiltered. The filter cake was washed with 1 M hydrochloric acid solutionand chilled ethanol (10 ml) and dried in vacua to give 2.6 g (73%) ofproduct, mp 252-253° C.

[0162] Analysis:

[0163] Calculated for C₁₆H₂₄ClN₃O: 62.02%C 7.81%H 13.56%N

[0164] Found: 62.15%C 8.09%H 13.61%N

EXAMPLE 188-Azaspiro[4,5]decane-1-[N′-(4-methoxy)phenyl-N′-methyl]hydrazonehydrochloride

[0165] To a solution of 8-azaspiro[4,5]decane-1-one hydrochloride (5.2g) in 95% ethanol (30 ml) was added acetic acid (1 ml) and1-(4-methoxy)phenyl-1-methylhydrazine (5.0 g), under nitrogen, withsining, The mixtur was heated on a steam bath for 2 hrs and wasconcentrated in vacuo. The residue was recrystallized from ethylacetate. The precipitate was titurated with ethanol/ethyl acetate andthen dichloromethane/petroleum ether to give 3.6 g (36%) of product, mp177-178° C.

[0166] Analysis:

[0167] Calculated for C₁₇H₂₆ClN₃O: 63.05%C 8.09%H 12.97%N

[0168] Found; 62.65%C 8.24%H 12.76%N

EXAMPLE 19 8-Azaspiro[4,5]decane-1-(N′-phenyl)hydrazone hydrochloride

[0169] To a solution of 8-azaspiro[4,5]decane-1-one hydrochloride (5.0g) in ethanol (15 ml) was added acetic acid (1 ml) and phenylhydrazine(2.85 g), under nitrogen, with stirring. The mixture was heated on asteam bath for 15 min, cooled to 0° C. and filtered. The filter cake waswashed with 1M hydrochloric acid solution and chilled ethanol (10 ml)and dried in vacuo to give 5.5 g (85%) of product, mp 261-262° C.

[0170] Analysis:

[0171] Calculated for C₁₅H₂₂CIN₃: 64.39%C 7.92%H 15.02%N

[0172] Found: 64.34%C 7.92%H 15.13%N

EXAMPLE 20 Ethyl 2cyano-1-imino-8-azaspiro[4,5]decane-8-carboxylatehemihydrate

[0173] To a solution of ethyl 4-(3-cyanopropyl)4cyano-1-piperidinecarboxylate (5 g) in tetrahydrofuran (75 ml) was addedlithium diisopropylamide (2.5 g) at −70° C., under nitrogen, withstirring. The reaction mixture was warmed to ambient temperature over 10min and heated at reflux for 90 min. The reaction mixture was cooled toambient temperature, neutralized with 5% hydrochloric acid and extractedwith ethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate, filtered, and the filtrate was concentrated in vacuo. Theresidue was recrystallized from chloroform/petroleum ether to afford 1.8g (36%) of product, mp 215-216° C.

[0174] Analysis:

[0175] Calculated for C₁₃H₂₀N₃O₃: 60.45%C 7.80%H 16.27%N

[0176] Found: 60.62%N 7.51%H 16.01%N

EXAMPLE 21 8-Azaspir[4,5]decane-1-one hydrochloride

[0177] A solution of 4-cyano-1-imino-8-azaspiro [4,5]decane (2.6 g) in6N hydrochloric acid (100 ml) was heated at 95° C. overnight. Thereaction mixture was concentrated in vacuo. The residue was flashchromatographed (silica gel), eluting with 20% methanol/dichloromethane.The appropriate fractions were collected and concentrated. The residuewas recrystallized from ethanol to give 0.8 g (55%) of product, mp212-213° C.

[0178] Analysis:

[0179] Calculated for C₉H₁₆ClNO: 56.99%C 8.50%H 7.38%N

[0180] Found: 56.87%C 8.34%H 7.31 %N

EXAMPLE 22 4-Acetamido-N-ethoxycarbonylpiperdine

[0181] A solution of 4-acetamidopiperidine (20.7 g), sodium bicarbonate(10.6 g) and water (300 ml) was cooled to 0° C., and 17.7 g of ethylchloroformate was added dropwise, with stirring. Upon completion of theaddition, the reaction mixture was allowed to warm to ambienttemperature and was diluted with water and ethyl acetate. The layerswere separated, and the organic layer was washed with saturated sodiumchloride solution, dried over anhydrous magnesium sulfate and filtered.The filtrate was evaporated to give 32.2 g (100%) of product.

EXAMPLE 23 4-Cyano-N-ethoxycarbonylpiperidine

[0182] A mixture of 4-acetamido-N-ethoxycarbonylpiperidine (17.0 g) andacetonitrile (200 ml) was cooled to 0° C., and 15.5 g of thionylchloride was added dropwise, under nitrogen, with stirring. The reactionmixture was allowed to warm to ambient temperature. To the reactionimixture was added 2-propanol (20 ml) and the mixture was heated underreflux for 1 hr. Ethyl acetate was added, the layers were separated, andthe organic phase was washed with 5% sodium bicarbonate solution, driedover anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. The residue was chromatographed on a preparatory liquidchromatograph, eluting with 4:1-heptane-ethyl acetate. The appropriatefractions were collected and evaporated to give 15 g of residue. A 4-gsample of the residue was distilled to give 3.5 g (84.6%) of product, bp130° C. (4 mm mercury).

We claim:
 1. A compound of the formula

wherein X is hydrogen, halogen, loweralkoxy, loweralkyl, hydroxy,trifluoromethyl and m is 1 or 2, or a group of the formula

wherein R is loweralkyl and R₃ is hydrogen or loweralkyl, R₁ is hydrogenor loweralkyl; R₂ is hydrogen, a group of the formula

wherein n is 1 or 2 and X and m are as above, a group of the formula

wherein X and m are as above, or a group of the formula

wherein X is as above, Y is hydrogen, or a group of the formula

wherein R₄ is hydrogen or loweralkyl and p is 2 or 3; the opticalisomers thereof; or the pharmaceutically acceptable acid addition saltsthereof.
 2. A compound according to claim 1 wherein R₂ is hydrogen.
 3. Acompound according to claim 1 wherein R₂ is a group of the formula


4. The compound according to claim 1 which is1,4-dihydrospiro[cyclopent[b]indole-3(2H), 4′-piperidine.
 5. Thecompound according to claim 1 which is1,4-dihydro-7-methoxy-4-methylspiro[cyclopent[b]indole-3(2H),4′-piperdine].
 6. The compound according to claim 1 which is1,4-dihydro-7-methoxyspiro[cyclopent[b]indole-3(2H), 4′-piperdine]. 7.The compound according to claim 1 which is1,4-dihydro-7-dimethylaminocarbonyloxy-4-methylspiro[cyclopent[b]indole-3(2H),4′-piperidine].
 8. The compound according to claim 1 which is1,4-dihydro-4-methylspiro[cyclopent[b]indole-3(2H), 4′-piperidine]. 9.The compound according to claim 1 which is1′-benzoyl-1,4-dihydrospiro[cyclopent[b]indole-3(2H), 4′-piperidine].10. The compound according to claim 1 which is1′-benzoyl-1,4-dihydro-7-methoxy-4-methylspiro[cyclopent[b]indole-3(2H),4′-piperidine].
 11. The compound according to claim 1 which is1,4-dihydro-7-methoxy4-methyl-1′-phenylmethylspiro[cyclopent[b]indole-3(2H),4′-piperidine].
 12. The compound according to claim 1 which is1,4-dihydro-7-hydroxy4-methyl-1′-phenylmethylspiro[cyclopent[b]indole-3(2H),4′-piperidine.
 13. The compound according to claim 1 which is1,4-dihydro4-methyl-7-methylaminocarbonyloxy-1′-phenylmethylspiro[cyclopent[b]indole-3(2H),4′-piperdine].
 14. The compound according to claim 1 which is1,4-dihydro-1′-(3-methoxyphenyl)methyl4-methylspiro[cyclopent[b]indole-3(2H),4′-piperidine].
 15. The compound according to claim 1 which is1,4-dihydro-1′-(4-methoxyphenyl)methyl4-methylspiro[cyclopent[b]indole-3(2H),4′-piperidine].
 16. The compound according to claim 2 which is1-[4-[3-(7-Fluoro-1,4-dihydrospiro[cyclopent[b]indole-3(2H),4′-piperidine]-1′-yl)propoxy]-3-methoxyphenyl]ethanonehydrate.17. A compound of the formula

wherein R₂ is hydrogen or loweralkyl: R₅ is hydrogen or loweralkyl; andX is hydrogen, halogen, loweralkoxy, loweralkyl, hydroxy ortrifluoromethyl and m is 1 or 2; the optical isomers thereof; or thepharmaccutically acceptable salt thereof.
 18. A compound according toclaim 17 which is 8-azaspiro[4,5]decane-1-(N′-phenyl)hydrazone.
 19. Thecompound according to claim 17 which is8-azaspiro[4,5]decane-1-[N′-(4-methoxy)phenyl-N′-methyl]hydrazone. 20.The compound according to claim 17 which is8-azaspiro[4,5]decane-1-[N′-(4-methoxy)phenyl]hydrazone.
 21. Thecompound according to claim 17 which is8-azaspiro[4,5]decane-1-[N′-(4-bromo)phenyl]hydrazone.
 22. A compound ofthe formula

wherein R₆ is loweralkyl; and R₇ is halogen or cyano.
 23. The compoundaccording to claim 22 which is ethyl4-(3-chloropropyl)4-cyano-1-piperidinecarboxylate.
 24. The compoundaccording to claim 22 which is ethyl4-(3-cyanopropyl)4-cyano-1-piperidinecarboxylate.
 25. The compoundaccording to claim 22 which is ethyl2-cyano-1-imino-8-azaspiro[4,5]decane-8-carboxylate hemihydrate.
 26. Thecompound which is 9-azaspiro[4,5]decane-1-one.
 27. A memory dysfunctionrelieving composition comprising an adjuvant and as the activeingredient, a memory dysfunction relieving effective amount of acompound of claim
 1. 28. A depression treating composition comprising anadjuvant and as the active ingredient, a depression treatment amount ofa compound of claim
 1. 29. A depression treating composition comprisingan adjuvant and as the active ingredient, a depression treatment amountof a compound of claim
 17. 30. A method of relieving memory dysfunctionin mammals comprising administering to a mammal requiring memorydysfunction relief, a memory dysfunction relieving effective amount of acompound of claim
 1. 31. A methiod of treating depression in mammalscomprising administering to a mammnal requiring depression treatment, adepression treatment effective amount of a compound of claim
 1. 32. Amethod of treating depression in mammals comprising administering to amammal requiring depression treatment, a depression treatment effectiveamount of a compound of claim 17.